Rheumatoid Arthritis (RA) demonstrates significant morbidity, mortality and economic impact. Although the spectrum of autoantibodies occurring in patients with established IRA is well known, the point of development of autoreactivity relative to clinical disease, and the pattern of autoantibodies that evolves over time, is poorly characterized. We hypothesize that pre-clinical evidence of RA-related autoantibodies can be detected in stored sera from individuals who subsequently develop RA at a higher frequency than in stored sera from matched healthy controls. We also believe that a pattern of autoreactivity may be apparent that will demonstrate evidence of intra- or inter-molecular epitope spreading against synovial or systemic antigens during this pre-clinical phase. The characteristics of the pre-clinical autoimmune response may also be associated with the severity of disease that develops. To address these hypotheses, we will utilize a unique resource within the United States Military, the Department of Defense Serum Repository (DODSR), that will allow us to identify and study multiple serum samples over time from individuals who are initially a symptomatic but who then develop RA. This Repository houses serial serologic specimens and contains relevant demographic and medical information. We propose the following Specific Aim. 1) Determine the relative prevalence, stability and characteritics of RA-related autoantibodies over time in stored sera from individuals who subsequently develop RA in comparison to their prevalence in stored sera from healthy controls. We will utilize both standard ELISA and nephelometric assays of RA-related autoantibodies in these pre-clinical serum samples as well as a newly developed synovial proteome microarray technology. We also hope that these studies will provide insights into the autoantigens and/or pathogens that might be involved in disease initiation. Finally, although not directly addressed in this study, we believe that prevention of disability in RA could be more successful if down-regulation of the process underlying joint destruction were carried out during this asymptomatic early phase of disease. In addition, there is evidence that early treatment initiation is associated with decreased mortality, suggesting that earlier diagnosis and treatment have substantial long-term benefits. It is our long-term objective that predictive factors determined by this and other related studies will be used in the future to identify individuals at high risk for IRA so that prevention or very early treatment strategies can be initiated.